Abstract
Neurons and neuroendocrine cells produce neuropeptides, which act as long-range signals to modulate organismal state and physiological function. In a few cases, neuropeptides have been thought to promote regeneration, but understanding this connection has been difficult due to the relatively poor regenerative capacity of most traditional model organisms. To test whether neuropeptides drive robust regeneration, we used the highly regenerative asexual planarian flatworm as a model. We began by investigating enzymes that cleave and process pre-propeptides to produce bioactive neuropeptides. We characterized 12 putative neuropeptide-processing enzymes and identified three enzymes, prohormone convertase 2 (pc2), carboxypeptidase E (CPE), and peptidylglycine alpha-hydroxylating monooxygenase (PHM-1) that regulate regeneration through their effects on stem cell differentiation and maintenance. We then investigated 51 of the 52 known neuropeptide-encoding genes in planarians, finding that 16 of these genes promote efficient regeneration and/or stem cell function. Our work indicates that diverse neuropeptides regulate endogenous pluripotent stem cells during homeostasis and in robust regeneration. Our data supports a key role for neuropeptide signaling in planarians to promote a pro-regenerative state, which could be valuable to mimic in regenerative therapies.